The goal of this project is to identify genes that are involved in the transition of prostate cancer cells from the androgen-sensitive non- metastatic state to the highly metastatic androgen independent state and determine their function. Second, we will determine how targeting these genes can decrease the development of metastatic prostate cancer. Since there is evidence that during this progression growth (survival) factors may interact to enhance metastatic potential as androgen control is lost, we will also study the interaction of a growth factor system (insulin-like growth factor) with changes in androgen sensitivity. We will address the hypothesis that: Progression to androgen-independent metastatic prostate cancer involves the activation of the androgen receptor (AR) or androgen regulated signaling pathways and genes by the insulin-like growth factor system. To perform these studies we have developed a unique prostate cancer cell system consisting of a tumorigenic but non-metastatic SV40- T immortalized prostate epithelial line, M2205, with both AR(+) and (-) clones and a highly metastatic subline M12 with AR(+) and (-) clones of which the AR(+) clones are no longer metastatic until the AR function is suppressed. We will perform the following specific aims: Aim 1. To identify alterations in gene expression as prostate cancer cells transition from an androgen-sensitive non-metastatic to an androgen-independent metastatic phenotype. Aim 2. To study the role of th IGF-1R and signaling pathways in progression to metastatic disease and the interaction with androgens and to characterize gene expression changes identified in aim 1 with regard to the functional mediation of androgen- independent growth. Aim 3. To identify approaches to the control of androgen-independent metastatic disease. For this purpose we wish to alter the expression of the IGF-1R and AR in the AI metastatic cell lines.